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GLYT1 encephalopathy

GLYT1 encephalopathy is a rare autosmal recessive, metabolic and genetic disorder which is caused by a mutation in the SLC6A9 gene.[1]

The main features of this disorder are: severely diminished muscle tone, respiratory failure, absence of neonatal reflexes, encephalopathy, reduced consciousness and unresponsiveness, also it can present with arthrogryposis/ligament laxity, and normal serum glycine.[2]

About 10 cases had been reported as of 2022.[3]

Symptoms

Someone with GLYT1 encphalopathy can present with facial dysmorphism, arthrogryposis and diminished muscle tone that progresses into muscle hypertonicity with so called startle-like clonus (which means that they have startle-like response to vocal and visual stimuli) and normal serum glycine level.[4][2]

Facial features of this disorder might include: thin eyebrows, saddle nose, retrognathism, long myopathic face, piggy noses, tent-shaped mouth, low-set ears.[3]

Diagnosis

Diagnosis of this disorder can be suspected by symptoms (such as: drowsiness, diminished muscle tone, and seizures) and by high glycine levels in cerebrospinal fluid and normal levels of enzymes and glycine in plasma, consequently diagnosis can be confirmed by genetic testing of GLYT1.[5]

Cause

This disorder is caused by a mutation in a gene SLC6A9, which encodes Sodium- and chloride-dependent glycine transporter 1 protein, which is located on chromosome 1.[6]

Pathophysiology

Glycine is the simplest amino acid, that doesn't have any stereoisomers.[7] Glycine participates in protein synthesis, but it can act as neurotransmitter, in the spinal cord and in the brain stem, it acts as inhibitory neurotransmitter by activating glycine channels.[8][9] Although it has excitatory effect in neocortex (by co-activating NMDAR).[10][11]

GLYT1 protein is located on astrocytes that are next to glycinergic neurons to clear glycine swiftly from the synaptic cleft.[12][13] Consequently, this mechanism is disrupted in this disease by hyperactivating NMDA receptors and glycine receptors.[14][15]

Treatment

GLYT1 encephalopathy doesn't have a cure and its management is supportive, and it requires a multidisciplinary team (that may consist of geneticists, paediatricians, physiotherapists, etc) to control symptoms.[16] One patient was treated sodium benzoate and ketamine, but it didn't show any results.[4]

Prognosis

This disorder is usually fatal in infancy. Only 2 patients survived till childhood (at the time of the article's publication).[16]

History

This disorder was first reported by Alfadhel and colleagues in 2016.[14]

See also

References

  1. ^ "Entry - #617301 - GLYCINE ENCEPHALOPATHY WITH NORMAL SERUM GLYCINE - OMIM". www.omim.org. Retrieved 2025-04-19.
  2. ^ a b Kurolap, Alina; Hershkovitz, Tova; Baris, Hagit N. (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "GLYT1 Encephalopathy", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 29190063, retrieved 2025-04-19
  3. ^ a b Daşar, Tuğba; Şimşek-Kiper, Pelin Özlem; Taşkıran, Ekim Zihni; Çağan, Murat; Özyüncü, Özgür; Deren, Özgür; Utine, Gülen Eda; Güçer, Kadri Şafak; Boduroğlu, Koray (2022-12-01). "A lethal and rare cause of arthrogryposis: Glyt1 encephalopathy". European Journal of Medical Genetics. 65 (12): 104631. doi:10.1016/j.ejmg.2022.104631. ISSN 1769-7212. PMID 36195292.
  4. ^ a b Kurolap, Alina; Armbruster, Anja; Hershkovitz, Tova; Hauf, Katharina; Mory, Adi; Paperna, Tamar; Hannappel, Ewald; Tal, Galit; Nijem, Yusif; Sella, Ella; Mahajnah, Muhammad; Ilivitzki, Anat; Hershkovitz, Dov; Ekhilevitch, Nina; Mandel, Hanna (2016-11-03). "Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine". The American Journal of Human Genetics. 99 (5): 1172–1180. doi:10.1016/j.ajhg.2016.09.004. ISSN 0002-9297. PMC 5097939. PMID 27773429.
  5. ^ Bhumika, S.; Basalingappa, Kanthesh M.; Gopenath, T. S.; Basavaraju, Suman (2022-11-17). "Glycine encephalopathy". The Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 58 (1): 132. doi:10.1186/s41983-022-00567-6. ISSN 1687-8329. PMC 9672649. PMID 36415754.
  6. ^ "Orphanet: SLC6A9-solute carrier family 6 member 9". www.orpha.net. Retrieved 2025-04-19.
  7. ^ Team, EBI Web. "glycine (CHEBI:15428)". www.ebi.ac.uk. Retrieved 2025-04-19.
  8. ^ Béchade, Catherine; Sur, Cyrille; Triller, Antoine (1994). "The inhibitory neuronal glycine receptor". BioEssays. 16 (10): 735–744. doi:10.1002/bies.950161008. ISSN 1521-1878. PMID 7980477.
  9. ^ Lynch, Joseph W. (2004-10-01). "Molecular Structure and Function of the Glycine Receptor Chloride Channel". Physiological Reviews. 84 (4): 1051–1095. doi:10.1152/physrev.00042.2003 (inactive 28 April 2025). ISSN 0031-9333. PMID 15383648.{{cite journal}}: CS1 maint: DOI inactive as of April 2025 (link)
  10. ^ Aragón, Carmen; López-Corcuera, Beatriz (2005-06-01). "Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion". Trends in Pharmacological Sciences. 26 (6): 283–286. doi:10.1016/j.tips.2005.04.007. ISSN 0165-6147. PMID 15925702.
  11. ^ He, Miaomiao; Wollmuth, Lonnie P. (2023-05-03). "Activation of excitatory glycine NMDA receptors: At the mercy of a whimsical GluN1 subunit". Journal of General Physiology. 155 (6): e202313391. doi:10.1085/jgp.202313391. ISSN 0022-1295. PMC 10163841. PMID 37133818.
  12. ^ Wang, Xiaolu; Yue, Ming; Cheung, Jason Pui Yin; Cheung, Prudence Wing Hang; Fan, Yanhui; Wu, Meicheng; Wang, Xiaojun; Zhao, Sen; Khanshour, Anas M.; Rios, Jonathan J.; Chen, Zheyi; Wang, Xiwei; Tu, Wenwei; Chan, Danny; Yuan, Qiuju (2024-01-16). "Impaired glycine neurotransmission causes adolescent idiopathic scoliosis". The Journal of Clinical Investigation. 134 (2). doi:10.1172/JCI168783. ISSN 0021-9738. PMC 10786698. PMID 37962965.
  13. ^ Eulenburg, Volker; Armsen, Wencke; Betz, Heinrich; Gomeza, Jesús (2005-06-01). "Glycine transporters: essential regulators of neurotransmission". Trends in Biochemical Sciences. 30 (6): 325–333. doi:10.1016/j.tibs.2005.04.004. ISSN 0968-0004. PMID 15950877.
  14. ^ a b Alfadhel, Majid; Nashabat, Marwan; Qahtani, Hanan Al; Alfares, Ahmed; Mutairi, Fuad Al; Shaalan, Hesham Al; Douglas, Ganka V.; Wierenga, Klaas; Juusola, Jane; Alrifai, Muhammad Talal; Arold, Stefan T.; Alkuraya, Fowzan; Ali, Qais Abu (2016-11-01). "Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans". Human Genetics. 135 (11): 1263–1268. doi:10.1007/s00439-016-1719-x. ISSN 1432-1203. PMC 5052303. PMID 27481395.
  15. ^ Mademont-Soler, Irene; Casellas-Vidal, Dolors; Trujillo, Alberto; Espuña-Capote, Núria; Maroto, Anna; García-González, Maria del Mar; Ruiz, María Dolores; Diego-Álvarez, Dan; Queralt, Xavier; Perapoch, Josep; Obón, María (2021). "GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms". American Journal of Medical Genetics Part A. 185 (2): 476–485. doi:10.1002/ajmg.a.61996. ISSN 1552-4833. PMID 33269555.
  16. ^ a b Alfallaj, Rayan; Alfadhel, Majid (2019-01-01). "Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review". Child Neurology Open. 6: 2329048X19831486. doi:10.1177/2329048X19831486. ISSN 2329-048X. PMC 6383083. PMID 30815509.